Note: Descriptions are shown in the official language in which they were submitted.
`` 12~Z~7Q
RAN 4008/329
The present invention relates to pyrrolo[3,4-d][2]-
benzazepine derivatives of the general formula
R
I
~ 4
--N
~ R5
IJ
wherein Rl and R3 are hydrogen, lower alkyl, hydroxy,
lower alkoxy or acyloxy and R2 and R4 are hydrogen
or Rl and R2 and/or R3 and R4 taken together are oxo
groups with the proviso that at least one oxo group
is present; R is hydrogen, lower alkyl, C2 to C7
: carboxylic acids and the esters and amides thereo~,
hydroxy C2 to C7 alkyl, amino C2 to C7 alkyl or
mono- or di-lower alkyl amino C2 to C7 alkyl; R5 is
halogen having an atomic number not greater than 35
or hydrogen; and R6 is halogen having an akomic
number not greater than 35 with the proviso that when
Rl or R3 is hydroxy, lower alkoxy or acyloxy, then R
is lower alkyl or hydrogen
and the N-oxides and the pharmaceutically acceptable salts
th`~ereof.
The compounds exhibit activity as sedative and anxio-
35 lytic agents.
Bt/25.3.83
.~
V~970
By the term "halogen having an atomlc number not
greater than 35" is meant bromo, chloro or fluoro except
as limited herein.
6 By the term "lower alkyl" is meant bobh straight and
branched chaln Cl to C7 hydrocarbon groups, preferably
Cl to C4 carbon-hydrogen radicals, such as methyl, ethyl,
propyl, isopropyl and the like.
By the term "acyloxy" is meant a radical derived from
an organic acid by the removal of the hydrogen atom i.e.,
radicals of the formula -O-I~R wherein R is Cl to C6 alkyl,
phenyl or hydrogen, eOg., acetyl, propionyl, butyryl,
15 benzoyl, etc.
By the term "C2 to C7 carboxylic acids and the esters
and amides thereof" is meant radicals of the formula -Cl to
C6 alkyl COR2l where R2l is hydroxy, lower alkoxy, amino or
20 amino which is mono- or di-substituted by lower alkyl.
The expression "pharmaceutically acceptable salts" is
used to include salts with both inorganic and organic
pharmaceutically acceptable acids, such as sulfuric acid,
25 hydrochloric acid, nitric acid, methansulfonic acid and
p-toluenesulfonic acid. Such salts can be formed quite
readily by those skilled in the art with the prior art and
the nature of the compounds to be placed in salt form in
view.
Preferred compounds within the scope of the present
invention are those of the formula I, i.e., the Schiff bases.
Further preferred compounds are those of the formula I
wherein R3 and R4 taken together are an oxo group. Still
further preferred compounds are those of formula I wherein
R2 is hydrogen, Rl is preferably hydrogen or lower alkyl,
more preferably hydrogen or methyl. The preferred meaning
of R is hydrogen or lower alkyl, more prefera~ly hydrogen
2970
or methyl. R5 is pre~erably halogen having an atomic number
not greater than 35.
From the above it follows that an especially preferred
group of compounds within the scope of the present inven-
tion are those of formula I, wherein R and R1 are hydrogen
or lower alkyl, preferably methyl, R2 is hydrogen, R3 and
R4 taken together are an oxo ~roup and R5 is halogen having
an atomic number not greater than 35.
Preferred compounds are:
8-chloro-6-(2-fluorophenyl)-3,4-dihydropyrrolo[3,4-d]-
[2]benzazepin-1~2H)-one,
8-chloro-6-(2-chlorophenyl)-3,4-dihydropyrrolo[3,4-d]-
[2]benzazepin-1(2H)-one,
8-chloro-3,4-dihydro-6-phenylpyrrolo[3,4-d]~2]benzaze-
pin-1(2H)-one,
: 8-chloro-6-(2-chlorophenyl)-3,4-dihydro-2-methyl-
Z0 pyrrolo[3,4-d][2]benzazepin-1(2H)-one,
8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1-hydroxy-
pyrrolo[3,4-d][2]benzazepin-3(2H)-one,
8-chloro-6-(2-chlorophenyl)-3,4-dihydro-3-hydroxy-
pyrrolo[3,4-d~[2]benzazepin-1(2H)-one,
8-chloro-6-(2-chlorophenyl)pyrroloC3,4-d][2]benzazepin_
1,3-(2H,4H)-dione,
8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo[3,4-d]-
[2]benzazepin-3(2H)-one-5-oxide,
8-chloro-6-(2-chlorophenyl)-3,4-dihydropyrrolo[3,4-d]-
30 [2]benzazepin-1(2H)-one-5-oxide,
8-chloro-6-(2-chlorophenyl)-1-ethyl-1,4-dihydropyrrolo-
[3,4-d][2]benzazepin-3(2H)-one,
8-chloro-6-~2-chlorophenyl)-1,4-dihydro-1-me~hyl-3-
oxo-2H-pyrrolo~3,4-d][2]benzazepine-2-acetic acid methyl
35 ester and
8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1-methyl-3-
oxo-2H-pyrrolo[3,4-d][2]benzazepine-2-acetamide.
~2~2~3~0
-- 4
~specially preferred compounds are: .
8-chloro-6-(2~fluorophenyl)-l,4-dihydropyrrolo~3,4-d]-
~2]benzazepin-3(2H)-one,
8-chloro-l,4-dihydro-6-phenylpyrrolo[3,4-d][2]benzaze-
pin-3(2H)-one,
8-chloro-6-(2-chlorophenyl)-l,4-dihydro-l,2-dimethyl-
pyrrolo~3,4-d]~2]benzazepin-3(2H)-one and
8-chloro-6-(2-chlorophenyl)-l,4-dihydro-2-(2-hydroxy-
10 ethyl)-l-methylpyrrolo~3~4-d][2]benzazepin-3(2H)-one~
The most preferred compounds are:
8-chloro-6-(2-chlorophenyl)-l,4-dihydropyrrolo[3,4-d]-
15 [2]benzazepin-3(2H)-one,
8-chloro-6-(2-chlorophenyl)-l,4-dihydro-l-methyl-
pyrrolo[3,4-d][2]benzazepin-3(2H)-one and
8-chloro-6-(2-chlorophenyl)-l,4-dihydro-2-methyl-
pyrrolo[3,4-d]~2]benzazepin-3(2H)-one.
The compounds of formula I, the N-oxides and the
pharmaceutically acceptable salts thereof can be prepared
in accordance with the invention
25 a) for preparing compounds of the formula I above wherein
Rl or R3 is hydrogen or lower alkyl and the remaining sub-
stituents are as above and the N-oxides thereof, by oxi-
dizing a compound of the formula
N
R~ t R31
~ ~ II
35 R6 ~ N
~ R5
~Z(~2970
wherein one of Rll and R3l is hydrogen and the other
is hydrogen or lower alkyl and R, R5 and R6 are as
above
with a peracid, or
b) for preparing compounds of the formula I above wherein
Rl or R3 is hydroxy and the remaining substituents are as
above or Rl and R2 and R3 and R4, respectively, are, when
taken together, oxo groups and the remaining symbols are
10 as above, by oxidizing a compound of formula I wherein R
or R3 is hydrogen and the remaining substituents are as
above, or a compound of the formula II above wherein Rll
and R3l are hydrogen, with a lead (IV) carboxylate in the
presence of a strong acid, or
c) for preparing compounds of the formula I abo~e wherein
Rl or R3 is acetoxy and the remaining substituents are as
above, by treating a compound of the formula I wherein R
or R3 is hydrogen and the remaining substituents are as
20 above, or a compound of the formula II above wherein Rll
: and R3l are hydrogen, with lead tetraacetate in acetic acid,
or
d) for preparing compounds of the formula I above wherein
25 Rl or R3 is acyloxy and the remaining substituents are as
: above, by treating a compound of formula I wherein Rl or
R3 is hydroxy and the remaining substituents are as above,
with a carboxylic anhydride in the presence of a base, or~
30 e) for preparing compounds of the formula I above wherein
Rl or R3 is lower alkoxy and the remaining substituents are
as above, by treating a compound of formula I wherein Rl
or R3 is acyloxy or hydroxy and the remaining substituents
are as above, or a compound of the formula
.
-- 6
~12 ~ ~ R12
III
~ =
~T--R5
`~
wherein R12 is acetoxy and R, R5 and R6 are as above
with a lower alkanol in the presence of a strong acid, or
1~ f) for preparing compounds of the formula I above wherein
Rl or R3 is hydrogen or alXyl and the remaining substi-
tuents are as above, by desoxygenating an N-oxide of the
formula
R~ ~ R3
R2 ~ - / R4
6 ?
R ~ ~ ~
~5
...
l~ R2, R3, R4, R5 and R~ are as above
30 and, if desired,
g) by converting a compound of formula I into a pharma-
cautically acceptable salt or converting a pharmaceutically
acceptable salt of a compound of formula I into another
35 pharmaceutically acceptable sal~.
The oxidation of a compound of formula II with a
peracid according to process embodiment a) of the present
~;J
~2~ 70
process is performed in a manner known per se. Suitable
peracids for this oxidation step are peracids such as
m-chloroperben20ic acid, pertrifluoroacetic acid and the
like. Depending on the reaction conditions used, one will
obtain elther the corresponding compounds of formula I or
the N-oxides thereof. For obtaining the compounds of formu-
la I, the reaction is expeditiously performed in a lower
carboxylic acid such as acetic acid, trifluoroacetic acid,
propionic acid and the like or in a mixture of such a car-
10 boxylic acid with a suitable inert solvent such as achlorinated hydrocarbon, e.g., methylene chloride, an aro-
matic hydrocarbon, e.g., benzene, toluene, and the like,
in the presence of a strong mineral acid such as sulfuric
acid and the like. In case a corresponding N-oxide is desi-
15 red, the reaction is conveniently performed in a suitableinert solvent such as a chlorinated hydrocarbon, e.g.,
methylene chloride, or an aromatic hydrocarbon, e.g.,
benzene, toluene and the like, in the absence of a strong
mineral acid. The oxidation of a compound of formula II is
20 preferably performed at a temperature between about 0C and
about room temperature. It should be noted that a mixture
of the l-oxo and 3-oxo compounds will be obtained when in
the starting material of formula II both Rll and R3l are
hydrogen. In case the oxidation is performed under strong
25 acidic conditions, the 3-oxo compound will predominate
whereas the l-oxo compound will be the predominant product
when the reaction is performed in the absence of a strong
mineral acid. The mixture obtained can be separated accor-
ding to standard methods such as fractional crystallization
30 and chromatography.
The oxidation in accordance with process embodiment
b~ of the present process is also performed according to
methods known per se. In this oxidation, lead (IV) carboxy-
35 lates such as lead tetraacetate or lead (IV) trifluoroace-
tate in an inert solvent such as chlorinated hydrocarbons
such as methylene chloride or chloroform, and the like in
the presence of a stron~ acid such as trifluoroacetic acid
lZ~Z97~
-- 8
and the like can suitably be used. The reaction is prefera-
bly performed in a temperature range of from about 0C to
about room temperature. In the case of a compound of formu-
la II wherein Rll and R3l are hydrogen, a mixture of the
l-hydroxy-3-oxo, the 3-hydroxy-l-oxo and l,3~dioxo com-
pounds is obtained. The mixture thus obtained can be separa-
ted by standard chromatographic procedures.
Also, the reaction in accordance with process embodi-
10 ment c) of the present process is performed according toknown methods. Thus, the starting material can be reacted
with lead tetraacetate in acetic acid, preferably at about
room temperature. In case a compound of formula II wherein
Rll and R3l are hydrogen is used as starting material, a
15 mixture of the l-acet~xy-3-oxo and 3-acetoxy l-oxo com-
pounds and of a l,3-bis-acetoxy compound of formula III will
be obtained. The mixture obtained can be separated by
standard chromatographic procedures.
The reaction of a compound of formula I wherein Rl or
R3 is hydroxy with a carboxylic acid anhydride in accordance
with process embodiment d) of the present process is also
performed in a manner known per se, preferably in the
presence of a base such as pyridine, dimethylaminopyridine,
25 N-methylpiperidine and the like. Inert solvents which can
be used in this reaction are chlorinated hydrocarbons such
as methylene chloride, ethers such as tetrahydrofuran, and
the like. The reaction is conveniently performed at a
temperature in the range of about 0C to about room tempe-
30 rature.
The etherification in accordance with process embodi-
ment e) of the present process is performed in a manner
known per se, expediently by reacting a compound of formu-
35 la I wherein Rl or R3 is acyloxy, preferably acetoxy, or acompound of formula III, with an excess of a lower alkanol
containing a catalytic amount of a strong acid such as
methane sulfonic acid and the like. This reaction is pre-
~2970
g
ferably performed at a temperature between about 0C andabout room temperature.
The desoxygenation in accordance with process embodi-
ment f) of the present process is also performed according
to known methods, conveniently by treatlng a compound of
the ~ormula IA with a desoxygenating agent such as phos~
phorous trichloride or triphenylphosphine in an inert sol-
vent such as chlorinated hydrocarbons, e.g., methylene
10 chloride, aromatic hydrocarbons, e.g., toluene, ethars,
e.g., tetrahydrofuran, and the like at a temperature bet-
ween about room temperature and the reflux temperature of
the solvent.
The startlng materials of formula II are known or can
be prepared in an analogous manner to the preparation of
the known compounds. The following reaction schemes illus-
trate the preparation of these formula II compounds.
26
l~Z97~
-- 10 --
Scheme I
R6 _ CHCN ~ CN
S ~ R5
~1 / N
I V H
R ~ R ~ 0~ NH2
~ R5 ~ R5
IIa V
wherein R13 is hydrogen or lower alkyl and R5 and
R6 are as above.
IV
The compound of formula III can be reacted with an
a-tosyl alkylisocyanide in the presence of a base such as
sodium hydride using a mixture of dimethylsulfoxide and
an ether, such as diethylether, dloxane or tetrahydrofuran
as solvent. The reaction temperatures may range from about
0C to about 40C with about room temperature being pre-
ferred. The a--tosyl alkylisocyanides mentioned above may
be prepared following the teaching of van Leusen et al.,
10 Tetrahedron Letters, 3487 (l975).
IV --~ IIa
The compound of formula IV can be reacted with hydro-
gen at pressures ranging from about atmospheric pressure to
15 five atmospheres in the presence of a transition metal
catalyst, such as Raney nickel using glacial acetic acid
as solvent. The reaction temperature is suitably about
room temperature.
The first formed ring open amine is not isolated but
cyclizes spontaneously to product IIa.
IV --~ V
The compound of formula IV can be reacted with a metal
25 hydride reducing agent, such as lithium aluminum hydride in
an etherial solvent such as tetrahydrofuran. The reaction
temperature may range from about -20C to about room tempe-
rature, with about 0C being preferred.
30 V ~ IIa
The compound of formula V can be reacted with manganese
dioxide in an ether solvent, such as tetrahydrofuran or
another suitable solvent, such as toluene. The resulting
amine thus formed cyclizes spontaneously to product IIa.
35 The reaction temperature may range from about room tempera-
ture to the boiling point of the solvent, with about 40C
being preferred.
~LZ~;~970
- 12 -
Scheme II
H
R6~
~R5
IIa'
////// I ~\\'
32
[~3 R5 ~ R5
IIa" IIb
wherein R14 and R32 are lower alkyl and R5 and R6
are as above.
Z970
- 13 -
IIa' --~ IIa" + IIb
The compound of formula IIa' can be reacted with one
equivalent of a strong base such as lithium diisopropyl-
amide at between about -80C to about 0C, with about -20C
being preferred. The resulting anion is treated with the
desired alkylating agent, such as a lower alkyl halide or
sulfonate. A mixture of formula IIa" and IIb isomers results
which can be separated by standard column chromatography
procedures.
97~)
- 14 -
Scheme III
Rn
~6 - ~ ~3
R5 \
V ~ ~c,~ ,cocr~
tCH2)n+lN \ I 2n ~ ~ N~
R
~g ~ ~
(C~2~nCOoH ~ 32~n.~.lH
R J~ R6J~
wherein R" is lower alkyl, R7 is lower alkyl, R8 and Rg
are hydrogen or lower alkyl and n is an lnteger from 1
to 6 and R11, R31, R5 and R6 are as above.
:~LZ~2!3 7~
- 15 -
IIc ~ IIh --~ IIj
A compound of the formula IIc can be reacted with a
halo ester such as ethyl bromoacetate or ethyl 3-bromopro-
pionate in the presence of a base such as an alkali metal
alkoxide in a polar solvent such as dimethyl sulfoxide or
dimethylformamlde. The reaction temperature may range from
about -20C to about room temperature, with about 0C being
preferred. If desired, the product of formula IIh thus
obtained may be treated with an alkali metal carbonate or
10 hydroxide in an aqueous ethereal solvent, such as tetra-
hydrofuran. Subsequent addition of a strong mineral acid
thus yields the corresponding carboxylic acid of formula IIj.
IIh ~ IIf
A compound of the formula IIh can be xeacted with
ammonia or a mono- or di-lower alkyl amine and a catalytic
amount of its hydrochloride saLt with a Cl to C4 alcohol
solvent. The reaction is usually conducted at about 100C
using a pressure apparatus to contain the volatile reactants.
IIh
A compound of the formula IIh can be reacted with a
metal hydride such as lithium aluminum hydride in an etheral
solvent such as tetrahydrofuran or dioxane. The reaction
25 temperature may range from about -80C to about room tempe-
rature, with about 0C being preferred.
IIc --~ IIg
A compound of the formula IIc can be reacted with a
30 compound of the formula
/R8
X-(CH2)n+l-N \ VI
Rg
wherein X is halide or sulfonate and R8, Rg and n
are as above
in the presence of a base such as an alkali metal alkoxide
."
~2~70
- 16-
in a polar solvent such as dlmethylsulfoxide or dimethyl-
formamide. The reaction temperature may range from about
-20C to about room temperature with about room temperature
being preferred.
IIc ~ IIe
A compound of the formula IIc can be reacted with a
base such as an alkali metal alkoxide, e.g., potassium or
sodium methoxide, followed by an alkylating agent, such as
10 a lower alkyl halide or sulfonate in a polar aprotic sol-
vent such as dimethylformamide or dimethyl sulfoxide. The
reaction temperature may range from about 0C to about room
temperature, with about 0C being preferred.
1~ IIf --~ IIg or IIh --~ IIi
A compound of the formula IIf or IIh is reacted with
a metal hydride reducing agent, such as lithium aluminum
hydride in an ether solvent, such as tetrahydrofuran. The
reaction temperature may range from about -20C to about
20 room temperature, with about 0C being preferred.
IIc ~
A compound of formula IIc can be reacted in the
presence of a base such as an alkali metal alkoxide, and
25 dimethylformamide or dimethyl sulfoxide with a compound of
the formula
( 2)n+1 VII
wherein Z is a hydroxy protecting group and X and n
are as above.
Suitable hydroxy protecting groups include the tetra-
hydropyranyl ether group. Subsequent treatment with aqueous
35 acid yields the desired end product.
~Z~ 70
- 17 -
IIc -~ IIf
A compound of formula IIc can be reacted with a com-
pound of the formula
~; R8
~ N-C0-(CH2)n-X VIII
wherein X, R8, Rg and n are as above
10 in the presence of a base such as an alkali metal alkoxide,
and dimethylformamide or dimethylsulfoxide.
The compounds of the invention are useful as pharma-
ceuticals and are characterized by activity a- sedatives
1~ and anxiolytic agents. These compounds can be used in the
form of conventional pharmaceutical preparations; for
example, the aforesaid compounds can be mixed with conven-
tional organic or inorganic, inert pharmaceutical carriers
suitable for parenteral or enteral administration such as,
20 for example, water, gelatin, lactose, starch, magnesium
stearate, talc, vagetable oil, gums, polyalkylene glycols,
Vaseline or the like. They can be administered in conven-
tional pharmaceutical forms, e.g., solid forms, for example,
tablets, dragees, capsules, suppositories or the like, or
25 in liquid forms, for example, solutions, suspensions or
emulsions. Moreover, the pharmaceutical compositions con-
taining compounds of this invention can be subjected to
conventional pharmaceutical expedients such as steriliza-
tion, and can contain conventional pharmaceutical excipients
30 such as preservatives, stabilizing agents, wetting agents,
emulsifying agents, salts for the adjustment of osmotic
pressure, or buffers. The compositions can also contain
other therapeutically active materials.
A suitable pharmaceutical dosage unit can contain from
about 0.1 to about 500 mg of the compounds of the invention
with a dosage range of from about 0.1 mg to about 100 mg
being preferred for oral administratisn and a dosage range
312029~0
- 18 ~
of from about 0.1 mg to about 50 mg being preferred for
parenteral adminlstration. However, for any particular sub-
ject, the specific dosage regimen should be adjusted accor-
ding to individual need and the professional judgment of
the person administering or supervising the administration
of the aforesaid compounds. It is to be understood that
the dosages set forth herein are exemplary only and that
they do not, to any extent, limit the scope or practice of
this invention.
The term "dosage unit" as employed throughout this
specification refers to pharmaceutically discrete units
suitable as unitary dosages for mammalian subject each
containing a predetermined quantity of active material cal-
16 culated to produce the desired therapeutic effect in asso-
ciation with the required pharmaceutical diluent, carrier
or vehicle.
The following data is indicative of the pharmacological
20 activities of the compounds of the invention utilizing
pharmacological tests well-known in the art.
H-Diazepam Binding Assay
The Assay acts as a screen for antianxiety drugs.
Rat brain cortical fragments are prepared and the
binding procedures performed as described by Mohler and
Okada (Life Sciences, 20, 2101, 1977) except that Tris
30 buffer is substituted for Krebs buffer. Drugs are assayed
in triplicate. Radioactivity is measured by liquid scin~-
tillation counting. The results are expressed as IC50
(nM), i.e. the concentrations required to inhibit the
bindung by 50%.
3~ Activity of Standard Drugs: IC50 (nm)
Diazepam 5.0
Flunitrazepam1.8
Flurazepam 15.6
~Z{~Z~3170
-- 19 _
Results obtained with compounds of the
invention: IC5~ (nM)
8-chloro-6-(2-chlorophenyl)-1,4-dihydro-2-
5 methylpyrxolo~3,4-d]~2]benzazepin-3(2H)-one
~LD50 ~ 800 mg/kg (po)(mice)] 0.006
8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1-
methylpyrrolo~3,4-d]~2]benzazepin-3(2H)-one
10 ~LD50 ~ greater than lQ00 mg/kg (po)(mice)] 1.0
8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo-
[3,4-d]~2]benzazepin-3(2H)-one
0.25 molar hydrate micronized
15 [LD50 ~ greater than 1000 mg/kg (po)(mice)] 0.003
8-chloro-6~(2-chlorophenyl)-1,4-dihydropyrrolo-
[3,4-d]~2~benzazepin-3(2H)-one
~LD50 ~ 300 mg/kg (po)(mice)] 0.002
Intravenous Antimetrazol-Test
The test evaluates anticonvulsant agents and is consi-
dered to be predictive of anxiolytic activites.
Male mice, 45-54 days old, housed in facilities for
one week an food-deprived for about 24 hours, are used in
this test. The test compound, dispersed in 5% acacia, is
administered orally to mice, 3 animals being used per dose
30 level. One hour later, metrazol is administered intravenously
at 70 mg/kg (convulsant dose 100 mg/kg) and the animals are
observed 30 seconds for protectlon against convulsions.
The number of animals protected from convulsions is deter-
mined. The dose at which 50% of the animals are protected
35 from convulsive seizures is expressed as the ED50. The
approximate ED50 is calculated by the method of Miller and
Tainter (Proc. Soc. Exp. Biol. Med. 57:261, 1944).
,.~,,1
~LZC~Z~7~
Activity of Standard Drugs:ED50 mg/kq po
Chlordiazepoxide 3.9
Diazepam 1.0
5 Sodium Phenobarbital 19
Results obtained with compounds of
the invention: ED50 m~//kq po
10 8-chloro-6-~2-chlorophenyl)-l~4-dihydr
2-methylpyrrolo[3,4-d][2]benzazepin-
3(2H)-one 0.08
8-chloro-6-(2-chlorophenyl)-1,4-dihydro-
15 1-methylpyrrolo[3,4-d][2]benzazepin-
3(2H)-one 0.08
8-chloro-6-(2-chlorophenyl)-1,4-dihydro-
pyrrolo~3,4-d]~2]benzazepin-3(2H)-one
20 0.25 molar hydrate micronized 0.07
8-chloro-6-(2-chlorophenyl)-1,4-dihydro-
pyrrolo[3,4-d][2]benzazepin-3(2H)-one 0.03
The following examples are illustrative of the inven-
tion but are not meant to limit such invention.
,t~
1` ~2~2~0
- 21 -
Example 1
a) To a solution of 5.0 g of cupric sulfate in 3 liters
of concentrated ammonium hydroxide solution were added
300 g (4.6 mol) of activated zinc dust and 100 g (0.42 mol)
of 2-benzoyl-4-chlorobenzoic acid. The mixture was refluxed
for 3 days, during which the volume was maintained by the
addition of concentrated ammonium hydroxide solution. The
mixture was cooled, and the excess zinc was removed by
10 filtration. The filtrate was acidified by the addition of
concentrated hydrochioric acid to a pH of 3. The resulting
precipitate was collected by filtration and dried to con-
stant weight to give 2-benzyl-4-chlorobenzoic acid as a
white solid, mp 142-144C.
b) To a solution of 28.4 g (0.75 mol) of lithium alu-
minum hydride in 800 ml of ether, which was cooled to 0C,
were addeddropwise 85.1 g (O.345 mmol) of 2-benzyl-4-chloro-
benzoic a~id in 250 ml of ether. The mixture was allowed to
2~ warm to room temperature and was stirred for 2 hours. The
excess lithium aluminum hy~ride was discharged by the addi-
tion of 28.5 ml of water, 28.5 ml of 10% aqueous sodium
hydroxide solution, and 85.5 ml of water. The precipitate
was removed by filtration, and the filtrate was dried over
26 sodium sulfate. Removal of the ether at reduced pressure
gave 2-benzyl-4-chlorobenzyl alcohol as a colorless oil
which crystallized upon standing, mp 46.5-49C.
c) To a suspension of 238 g (1.1 mol) of pyridinium chloro-
30 chromate and 300 ml of methylene chloride were added 79.3 g
(0.34 mol) of 2-benzyl-4-chlorobenzyl alcohol. The mixture
was stirred at room temperature for 2 hours. The chromium
salts were precipitated by the addition of 2.4 liters of a
1:1 mixture of ether and petroleum ether, and the preci-
35 pitate was removed by filtration through Celite. The solventwas removed at reduced pressure to give 2-benzyl-4 chloro-
benzaldehyde as a yellow oil, which was used without further
purification.
*Trademark
r~
i ~z~70
_ 22 -
d) To a suspension of 10.5 g (0.437 mol) of mineral oil
free sodium hydride in 1.2 liters of tetrahydrofuran were
added dropwise 58.4 g (0.328 mol) of diethylcyanomethyl
phosphonate. After the hydrogen evolution had ceased (ca
60 min.), 69.4 g (0.3 mol) of 2-benzyl-4-chlorobenzaldehyde,
in 75 ml of tetrahydrofuran, were added dropwise. The mix-
ture was stirred overnight at room temperature. The tetra-
hydrofuran solution was decanted and concentrated at room
temperature. The residue was partitioned between 2 liters
10 of water and 1.5 liters of ether. The ether solution was
separated, washed with water, and dried over sodium sulfate.
The ether was removed at reduced pressure to give 3-~2-
benzyl-4-chlorophenyl]-2-propenenitrile as a yellow oil
which was used without further purification.
e) A mixture of 2~.8 g (0.14 mol) of 3-[2-benzyl-4-chloro-
phenyl] -2-propenenitrile, 50 g (0.5 mol) of chromlum
trioxide, 100 ml of methylene chloride, and 300 ml of acetic
acid was stirred at room temperature overnight. The excess
20 chromium trioxide was discharged by the slow addition of
30 ml of ethanol. The mixture was diluted with 800 ml of
water and extracted with S00 ml of ether. The ether solution
was washed with water, saturated aqueous sodium bicarbonate,
and saturated aqueous sodium chloride. The ether solution
25 was dried over anhydrous sodium sulfate and concentrated at
reduced pressure to give 3-(2-benzoyl-4-chlorophenyl)-2-
propenenitrile as a yellow oil.
A sample of the product was purified by preparative
30 layer chromatography (silica gel, 2 mm; 1:1 mixture of
methylene chloride and pentane) to give a white solid,
mp 87-89C.
3-(2-~enzoyl-4-chlorophenyl)-2-propenenitrile was also
35 prepared as follows:
f) A solution of 92.7 g (0.4 mol) of 2-amino-5-chloro-
benzophenone in 250 ml of acetonitrile was added to a
. . ,~.1
~Z~Z~7~
- 23 -
mixture of 70 g (0.52 mol) of cupric chloride, 65 g (0.63
mole) o~ t-butylnitrite, 500 ml of acrylonitrile and 500 ml
of acetonitrile. When the addition was complete, stirring
at room temperature was continued for 2 hours. The mixture
was diluted with 80 ml of 6N hydrochloric acid and 1500 ml
of water, extracted with ether and dried over anhydrous
sodium sulfate. The ether solution was concentrated at
reduced pressure to give a brown oil, which contained the
end product, a,4-dichloro-2-(benzoyl)benzenepropanenitrile,
10 and 2,5-dichlorobenzophenone. Trituration of the oil with a
mixture of ether and petroleum ether gave the end product
as a tan solid. Recrystallization of a small portion of the
end product from a mixture of ether and petroleum ether
gave pale yellow needles, mp 69-71C.
g) A mixture of 50.9 g (0.168 mol) of a,4-dichloro-2-
(benzoyl)benzenepropanenitrile, 17 g tO.14 mol) of potassium
carbonate, SO.9 g (0.5 mol) of potassium bicarbonate and
510 ml of dimethyl sulfoxide was stirred at room tempera-
20 ture for 48 hours. The mixture was diluted with 1.5 litersof water, and the resulting precipitate was collected by
filtration. Recrystallization from a mixture of methylene
chloride and ether gave 3-(2-benzoyl-4-chlorophenyl)-2-
propenenitrile as off-white prisms, mp 89-91C.
* * *
h) A mixture of 10.7 g (40 mmol) of 3-(2-benzoyl-4-chloro-
phenyl)-2-propenenitrile, 5.3 g (38 mmol) of tosylmethyl
isocyanide, 75 ml of dim~thyl sulfoxide and 150 ml of ether
were added dropwise to a suspension of 3.7 g (77 mmol) of
30 50% sodium hydride in mineral oil and 170 ml of ether. When
the addition was complete, stirring was continued for
2 hours. The mixture was diluted with water, and the ether
layer was separated. The aqueous solution was extracted
with ether. The combined ether extracts were washed with
35 water, dried over anhydrous sodium sulfate and concentrated
at reduced pressure to give a dark green oil. Purification
by column chromatography (800 g silica gel; eluent, 5%
ether in methylene chloride) gave 4-~2-benzoyl-4-chloro-
"
2~7~)
phenyl~-lH-pyrrole-3-carbonitrile as off-white prisms,
mp 175-177C.
i) A mixture of 4.0 g (13 mmol) of 4-[2-benzoyl-4-chloro-
phenyl]-lH-pyrrole-3-carbonitrile, 4 g of Raney nickel, and
300 ml of acetic acid were hydrogenated on a Parr appara-
tus for 4 hours. The Raney nickel was removed by filtration,
and the filtrate was diluted with 400 ml of ice water. The
acetic acid was neutralized with sodium bicarbonate, and
10 the resulting solution extracted with methylene chloride.
The methylene chloride solution was washed with water and
dried over sodium sulfate. Concentration of the methylene
chloride solution gave a yellow solid. Recrystallization
from methylene chloride/ether gave 8-chloro-6-phenyl-2H,4H-
15 pyrrolo[3,4-d][2]benzazepine as white solid, mp 203-206C.
j) In one portion, 4.0 g (13.6 mmol) of 8-chloro-6-phenyl-
2H,4H-pyrrolo[3,4-d][2]benzazepine were added to a mixture
of 3.4 g (15.7 mmol) of m-chloroperbenzoic acid in 100 ml
20 of 2% concentrated sulfuric acid in acetic acid and the
resulting mixture was stirred for 1 hour. The excess per-
acid was discharged by the addition of saturated aqueous
sodium bisulfite solution, and the mixture was concentrated
at reduced pressure. The residue was partitioned between
25 methylene chloride and water and neutralized with concen-
trated ammonium hydroxide solution. The methylene chloride
solution was washed with brine, dried over anhydrous sodium
sulfate and concentrated at reduced pressure to a dark
residue. Purification of the residue by column chromato-
30 graphy (silica gel, 100 g; eluent 5% methanol in methylenechloride) gave after crystallization from ethyl acetate
8-chloro-1,4-dihydro-6-phenylpyrrolo[3,4-d][2]benzazepin-
3(2H)-one as pale yellow prisms, mp 205-208C.
Thin layer chromatography of the crystallization fil-
trates indicated the presence of the isomeric 8-chloro-
3,4-dihydro-6-phenylpyrrolo~3,4-d][2]benzazepin-1(2H)-one.
~2~Z97~
- 25 -
Example 2
a) ~he preparation of a,4-dichloro-2-(2-fluorobenzoyl)-
benzenepropanenitrile was conducted in the same manner as
S the preparation of a,4-dichloro-2-(benzoyl)benzenepropane-
nitrile described in Example lf) to give pale yellow prisms,
mp 94-95C.
b) The preparation of 3-[2-(2-fluorobenzoyl)-4-chloro-
10 phenyl]-2-propenenitrile was conducted in the same manner
as the preparation of 3-~2-benzoyl-4-chlorophenyl)-2-pro-
penenitrile described in Example lg) to give off-white
prisms, mp 137-139C.
3-~2-(2-Fluorobenzoyl)-4-chlorophenyl]-2-propenenitrile
was also prepared as follows:
c) A solution of 5.0 g (14 mmol) of 5-chloro-2'-fluoro-2-
iodobenzophenone, 2 ml (14.3 mmol) of triethylamine, 2 ml
20 (30 mmol) of acrylonitrile and 35 mg (1.5 mmol) of palla-
dium acetate was refluxed under an atmosphere of argon for
16 hours. The mixture was diluted with 100 ml of lN hydro-
chloric acid and the resulting precipitate was collected
by filtration. The precipitate was washed with ether and
?5 air dried to give 3-[2-(2-fluorobenzoyl)-4-chlorophenyl]-
2-propenenitrile as an off-white solid,mp 130-133C.
* * *
d) The preparation of 4-~2-(2-fluorobenzoyl)-4-chloro-
phenyl]-lH-pyrrole-3-carbonitrile was conducted in the same
30 manner as the preparation of 4-[2-benzoyl-4-chlorophenyl]-
lH-pyrrole-3-carbonitrile described in Example lh) to give
off-white prisms, mp 177-179C.
e) A mixture of 3.0 g (9 mmol) of 4-~2-(2-fluorobenzoyl)-
3S 4-chlorophenyl]-lH-pyrrole-3-carbonitrile, ca 3 g of Raney
nickel and 150 ml of glacial acetic acid was hydrogenated
on a Parr aparatus at 50 psi for 6 hours. The Raney nickel
was removed by filtra-tion, and the acetic acid was removed
:~2~;Z970
- 26 -
at reduced pressure to give a yellow oil. The yellow oil
was poured on to ice, basified with ammonium hydroxide
solution and extracted with methylene chloride. The methy-
lene chloride solution was drled over anhydrous sodium
sulfate and concentrated at reduced pressure to give tan
crystals. Recrystallization from a mixture of ether and
methylene chloride gave 8-chloro-6-(2-fluorophenyl)-2H,4H-
pyrrolo[3,4-d][2]benzazepine as cream-colored prisms,
mp 197-199C.
f) In one portion, 5.0 ml (42.1 mmol) of 30% hydrogen
peroxide solution was added to 100 ml of a 1% solution of
concentrated sulfuric acid in acetic acid. After stirring
for 1 hour, S.0 g (15.0 mmol) of 8-chloro-6-(2-fluoro-
15 phenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine were added, and
the resulting mixture was stirred for 4 hours. The excess
peracid was discharged by the addition of saturated aqueous
sodium bisulfite solution, and the mixture was concentrated
at reduced pressure. The residue was partitioned between
20 methylene chloride and water and basified with concentrated
ammonium hydroxide solution. The methylene chloride solution
was washed with brine, dried over anhydrous sodium sulfate
and concentrated at reduced pressure to give 5.0 g of a
residue. Purificaticn by HPLC (silica gel; eluent, 3%
25 methanol in methylene chloride) gave in the first product
band after crystallization from ethyl acetate 8-chloro-6-(2-fluoro-
phenyl)-3,4-dihydropyrrolo[3,4-d][2]benzazepin-1(2H)-one as pale yellow
prisms, mp 223-225C.
F~rther elution gave in the second product band after crystalli-
zation from ethyl acetate 8-chloro~6-(2-fluorophenyl)-1,4-dihydropyrro-
10[3,4-d][2]benzazepin-3(2H)-one as colorless prisms, mp 217-218C.
Example 3
a) The preparation of a,4-dichloro-2-(2-chlorobenzoyl)-
benzenepropanenitrile was conducted in the same manner as
the preparation of a,4-dichloro-2-(benzoyl)benzenepropane-
lZ~7~
nitrile described in Example lf) to give off-white prisms,
mp 102-103C.
b) The preparation of 3-[2-(2-chlorobenzoyl)-4-chloro-
phenyl]-2-propenenitrile was conducted in the same manner
as the preparation of 3-(2-benzoyl-4-chlorophenyl)-2-pro-
penenitrile described in Example lg) to give o~f-white
prisms, mp 140-141~C.
10 c) The preparation of 4-[2-(2-chlorobenzoyl)-4~chloro-
phenyl]-lH-pyrrole-3-carbonitrile was conducted in the same
manner as the preparation of 4-~2-benzoyl-4-chlorophenyl]-
lH-pyrrole-3-carbonitrile described in Example lh) to give
off-white prisms, mp 182-184C.
1~
d) The preparation of 8-chloro-6-(2-chlorophenyl)-2H,4H-
pyrrolo[3,4-d~[2]benzazep~ne was conducted in the same
manner as the preparation of 8-chloro-6-t2-fluorophenyl)-
2H,4H-pyrrolo[3,4-d]~2]benzazepine described in Example 2e)
to give cream-colored prisms, mp 204-206C.
e) In one portion, 10.0 g (30.5 mmol) of 8-chloro-6-(2-
chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine were added
to a mixture of 7.6 g (35.2 mmol) of 80% m-chloroperbenzoic
25 acid in 225 ml of 2% concentrated sulfuric acid in acetic
acid and stirred at room temperature for 1 hour. The excess
peracid was discharged with saturated aqueous sodium bisul-
- fite solution, and the mixture was concentrated at reduced
pressure. The-residue was partitioned between methylene
30 chloride and water and basified with concentrated ammonium
hydroxide solution. The methylene chloride solution was
washed with brine, dried over anhydrous sodium sulfate, and
concentrated at reduced pressure to give 10.0 g of a yellow
residue. Crystallization from methylene chloride gave
35 8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo[3,4-d][2]-
benzazepin-3(2H)-one as pale yellow prisms, mp 243-244C.
Crystallization of the mother liquor from ethyl acetate gave
8-chloro-6-(2-chlorophenyl)-3,4-dihydropyrrolo[3,4-d][2]-
97~
~ 28 -
benzazepin-1(2H)-one as pale yellow prisms, mp 195-197C.
Example 4
In one portion, 9.8 ml of 30% hydrogen peroxide solu-
tion were added to 195 ml of a 1% solution of concentrated
sulfuric acid ln acetic acid. The mixture was stirred at
room temperature for 1 hour. In one portion, 9.8 g (30
mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4~-pyrroloC3,4-d]-
10 [2]benzazepine were added to the mixture and stirred at
room temperature for 2.5 hours. The excess peracid was
discharged by the addition o saturated aqueous sodium
bisulfite solution, and the mixture was concentrated at
reduced pressure. The residue was partitioned between
15 methylene chloride and water and basified with concentrated
ammonium hydroxide solution. The methylene chloride solu-
tion was washed with brine, dried over anhydrous sodium
sulfate, and concentrated at reduced pressure to give 10.0 g
of a yellow residue. Purification of the residue by column
20 chromatography (silica gel, 200 g; eluent, 5% methanol in
methylene chloride) gave in the first product band after
crystallization from ethyl acetate 8-chloro-6-(2-chloro-
phenyl)-3,4-dihydropyrroloC3,4-d][2]benzazepin-1(2H)-one as
pale yellow prisms, mp 195-197C. Further elution ga~e in
25 the second product band after crystallization from methy'
lene chloride 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-
pyrrolo~3,4-d][2]benzazepin-3(2H)-one as colorless prisms,
mp 243-244C.
Example S
In one portion, 15.0 g (69.5 mmol) of 80% m-chloro-
perbenzoic acid were added to a solution of 10.0 g (30.5
mmol) of 8-chloro-6-~2-chlorophenyl)-2H,4H-pyrrolo[3,4-d]-
35 C2]benzazepine in 350 ml of methylene chloride which wascooled to 0C. The reaction mixture was stirred at 0C
for 2.5 hours and then neutralized with saturated aqueous
sodium bicarbonate solution. The methylene chloride solution
~LZV2~7~
- 29 -
was washed with water, dried over anhydrous sodium sulfate
and concentrated at reduced pressure to yield 11.0 g of a
yellow residue. Purification of the residue by column chroma-
tography (silica gel, 150 g; 5% methanol in methylene chlo-
ride) gave a mixture of two products. Further purification
of the mixture by chromatography (alumina, 150 g; eluent,
5% methanol in methylene chloride) gave in the first pro-
duct band after crystallization from a mixture of ethyl
acetate and methanol 8-chloro-6-(2-chlorophenyl)-3,4-
10 dihydropyrrolo[3,4-d][2]benzazepin-1(2H)-one-S-oxide as
pale yellow prisms, mp 243-244C.
Further elution gave in the second product band after
crystallization from a mixture of ethyl acetate and metha-
nol 8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo[3,4-d]-
[2]benzazepin-3(2H)-one-5-o*ide as pale yellow prisms
solvated with 0.5 mole of methanol, mp 234-236C.
Example 6
a) A mixture of 33.9 g (0.11 mol) of 3-[2-(2-chloro-
benzoyl)-4-chlorophenyl]-2-propenenitrile, 20 g (0.96 mol)
of 1-tosylethyl isocyanide in 150 ml of dimethylsulfoxide
and 100 ml of ether was added dropwise to a suspension of
25 4-6 g (0.1 mol) of a 50% mineral Qil dispension of sodium
hydride in 100 ml of ether which was immersed in a room
temperature water bath. Stirring at room temperature was
continued for 2 hours. The mixture was diluted with 1.2
liters of water and 40 ml of lN hydrochloric acid and
30 extracted with methylene chloride. The methylene chloride
solution was washed with water, dried over anhydrous sodium
sulfate and concentrated at reduced pressure to give a dark
green oil. Crystallization from a mixture of ether and
petroleum ether gave 4-[4-chloro-2-(2-chlorobenzoyl)phenyl]-
35 5-methyl-lH-pyrrole-3-carbonitrile, mp 206-208C, as tan
crystals. Recrystallization from ether gave the desired
product as colorless crystals, mp 210-211C.
12~ 9~
A second crop of crystals consisting of 6-chloro-8-
(2-chlorophenyl)-1,8-dihydro-8-hydroxy-2-methylindeno-
[2,1-b]pyrrole-3-carbonitrile, mp 221-225C, was obtained
from ether. Recrystallization from ether gave pale yellow
prisms, melting at 232-237C.
b) A mixture of 8.5 g (24 mmol) of 4-[4-chloro-2-(2
chlorobenzoyl)phenyl]-S-methyl-lH-pyrrole-3-carbonitrile,
1 spoonful of Raney nickel and 250 ml of glacial acetic
10 acid was hydrogenated on a Parr apparatus at 55 psi over-
night. The catalyst was removed by filtration, and the
acetic acid was removed at reduced pressure. The residue
was diluted with water, basified with concentrated ammonium
hydroxide solution, and the resulting precipitate was collec-
15 ted by filtration. The precipitate was dissolved in tetra-
hydrofuran, dried over anhydrous sodium sulfate and concen-
trated at reduced pressure. The residue was crystallized
from a mixture of ether and petroleum ether to give off-
~hite crystals, mp 219 222C. Recrystallization from a
20 mixture of ether and methylene chloride gave 8-chloro-6-
(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine
as colorless crystals, mp 221-225C.
c) In one portion, 1 ml of 30% hydrogen peroxide was
25 added to 40 ml of a 1% solution of concentrated sulfuric
acid in acetic acid. After stirring for 1 hour, 2.0 g
(5.8 mmol) of 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-
pyrrolo[3,4-d][2]benzazepine were added, and the resulting
mixture was stirred at room temperature for 30 minutes. The
30 mixture was diluted with methylene chloride and neutrali-
zed with concentrated ammonium hydroxide solution. The
methylene chloride solution was dried over anhydrous sodium
sulfate and concentrated at reduced pressure to a dark
residue. Crystallization from ethyl acetate gave 8-chloro-
35 6-(2-chlorophenyl)-1,4-dihydro-1-methylpyrrolo[3,4-d][2]-
benzazepin-3(2H)-one as pale yellow prisms, mp 239-241C.
25~'7~1
- 31 -
Example 7
a) In one portion, 0.7 g (2.2 mmol) of 8-chloro-6-~2-
chlorophenyl)-2H,4H-pyrroloC3,4-d][2]benzazepine was added
to a solution of 0.3 g (2.6 mmol) of potassium t-butoxide
in 30 ml of dry dimethylformamide which was cooled to 0C.
After stirring for 15 minutes, 1.0 ml (16 mmol) of methyl
iodide was added, and the mixture was allowed to warm to
room temperature. Water was added, and the mixture was
10 extracted with methylene chloride. The methylene chloride
solution was washed with water, dried over anhydrous sodium
sulfate, and concentrated at reduced pressure to give a
yellow oil. Purification by column chromatography (silica
gel, 20 g; eluent, 5% ether in methylene chloride) and
15 recrystallization from a mixture of ether and petroleum
ether gave 8-chloro-6-(2-chlorophenyl)-2-methyl-2H,4H-
pyrrolo[3,4-d][2]benzazepine as colorless prisms, mp 167-
168C.
The methanesulfonate salt of 8-chloro-6-(2-chloro-
phenyl)-2-methyl-2H,4H-pyrrolo~3,4-d]~2]benzazepine was
prepared by adding equimolar amounts of the base compound
and methanesulfonic acid to`methanol and isolated by
precipitating the salt with the addition of ether. Re-
26 cr~stallization from a mixture of methanol and ether gave
the methanesulfonate salt as orange prisms, mp 200-203C.
b) In one portion, 1.4 ml of 30% hydrogen peroxide were
added to 56 ml of a 1% solu-tion of concentrated sulfuric
30 acid in acetic acid. After stirring for 1 hour, 2.8 g
(8.2 mmole) of 8-chloro-6-(2-chlorophenyl)-2-methyl-2H,4H-
pyrrolo[3,4-d][2]benzazepine were added, and the resulting
mixture was stirred at room temperature for 16 hours. The
mixture was concentrated at reduced pressure and the residue
35 was partitioned between methylene chloride and water. The
methylene chloride solution was neutralized with concentra-
ted ammonium hydroxide solution, washed with brine, dried
over anhydrous sodium sulfate and concentrated at reduced
` ~2~Z97~31 '
- 32 -
pressure to a yellow residue. Purification of the residue
by column chromatography (silica gel, 100 g; eluent, 5%
methanol in methylene chloride) gave in the first product
band after crystalliza~ion from ether 8-chloro-6-~2-chloro-
phenyl)-3,4-dihydro-2-methylpyrrolo~3,4-d]~2]benzazepin-
1(2H)-one as yellow prisms, mp 177-178C.
Further elution gave in the second product band after
crystallization from ether 8-chloro-6-(2-chlorophenyl)-1,4-
10 dihydro-2-methylpyrrolo[3,4-d]~2]benzazepin-3(2H)-one as
pale yellow prisms, mp 173-175C.
Example 8
15 a) A solution of 30.0 g (99.3 mmol) of 3-[2-(2-chloro-
benzoyl)-4-chlorophenyl~-2-propenenitrile and 23.0 g (103
mmol) of 1-tosylpropyl isocyanide in a mixture of 200 ml
of ether and 200 ml of dimethyl sulfoxide was added drop-
wise over a 20 minute period to an ice-cooled suspension of
20 6.7 g (140 mmol) of a 50% mineral oil dispersion of sodium
hydride in 145 ml of ether. Afte~ stirring for 1.5 hours,
500 ml of water were added dropwise, followed by 50 ml of
lN aqueous hydrochloric acid. The aqueous solution was
extracted with 3 x 500 ml of ether. The ether solutions were
25 combined and washed with 6 x 800 ml of water, dried over
anhydrous sodium sulfate, and concentrated at reduced
pressure to give 35.0 g of dark residue. Purification by
column chromatography (silica gel, 500 g; eluent, 50%
ether in petroleum ether) gave in the first product band
30 after crystallization from a mixture of ether and methylene
chloride 4-[-2-(2-chlorobenzoyl)-4-chlorophenyl]-5-ethyl-lH-
pyrrole-3-carbonitrile as off-white prisms, mp 163-164C.
Further elution gave in the second product ban~ after
crystallization from ether 6-chloro-8-(2-chlorophenyl)-2-
ethyl-1,8-dihydro-8-hydroxyindeno[2,1-b]pyrrole-3-carbo-
nitrile a`s colorless prisms, mp 172-174C.
,~:
lZ~2g7~
- 33 -
b) A mixture of 3.3 g (8.9 mmol) of 4-[2-(2-chloro-
benzoyl)-4-chlorophenyl]-5-ethyl-lH-pyrrole-3-carbonitrile,
O.S teaspoon of Raney nickel, and 100 ml of acetic acid was
hydrogenated on a Parr apparatus at 50 psi for 16 hours.
The Raney nickel was removed by filtration through a pad
of Celite, and the filtrate was concentrated at reduced
pressure to a dark residue. The residue was partitioned
between ice water and ether and basified wlth concentrated
ammonium hydroxide solution. The ether was removed at
10 reduced pressure, and the aqueous residue was stirred for
1 hour. The resulting precipitate was collected by filtra-
tion and dissolved in tetrahydrofuran. The tetrahydrofuran
solution was dried over anhydrous sodium sulfate and con-
centrated at reduced pressure to a residue which crystalli-
15 zed from ether to give 8-chloro-6-(2-chlorophenyl)-1-ethyl-
2H,4H-pyrrolo[3,4-d][2]benzazepine as yellow prisms, mp
251-253C. Recrystallization from a mixture of ether and
methylene chloride gave off-white prisms, mp 254-255C.
20 c) In one portion, 0.9 ml ~7.9 mmol) of 30% hydrogen
peroxide was added to 40 ml of a 1% solution of concentra-
ted sulfuric acid in acetic acid. After stirring for 1 hour,
2.0 g (5.6 mmol) of 8-chloro-6-(2-chlorophenyl)-1-ethyl-
2H,4H-pyrrolo[3,4-d][2]benzazepine were added, and the
25 resulting mixture was stirred for 20 minutes. The excess
peracid was discharged by the addition of saturated aqueous
sodium bisulfite solution, and the mixture was concentrated
at reduced pressure. The residue was partitioned between
methylene chloride and water and neutralized with concen-
30 trated ammonium hydroxide solution. The methylene chloridesolution was washed with brine, dried over anhydrous sodium
sulfate, and concentrated at reduced pressure. The resul-
ting oil was crystallized from ether to give 3-chloro-6-
(2-chlorophenyl)-1-ethyl-1,4-dihydropyrrolo[3,4-d][2]benza-
35 zepin-3(2H)-one as yellow prisms, mp 233-235C. Recrystalli-
zation from a mixture of ethyl acetate and methanol gave
colorless prisms, mp 236-237C.
~ ~ . 3
~Z(?Z97~
- 34 -
Example 9
a) In one portion, 2.0 g (5.8 mmol) of ~-chloro-6-~2-
chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d]~2]benzazepine
was added to an ice-cooled solution of 0.8 g (7.1 mmol)
of potassium t-butoxide in 20 ml of dry dimethylformamide.
After stirring at 0C for 10 minutes, 0.8 ml (12.8 mmol)
of methyl iodide was added and the resulting solution was
stirred for 20 minutes. The mixture was diluted with water,
10 and the resultlng precipitate was collected by filtration.
The solid was dissolved in methylene chloride, dried over
anhydrous sodium sulfate, and concentrated at reduced
pressure to give 8-chloro-6~(2-chlorophenyl)-1,2-dimethyl-
2H,4H-pyrrolo[3,4-d~[2]benzazepine as orange prisms, mp
200-202C. A sample was recrystallized from a mixture of
ether and methylene chloride to give pale yellow prisms,
mp 203-204C.
b) In one portion, 0.7 ml ~5.9 mmol) of a 30% hydrogen
20 peroxide solution was added to 33 ml of a 1% solutlon of
concentrated sulfuric acid in acetic acid. After stirring
for 1 hour, 1.8 g (5.0 mmol) of 8-chloro-6-(2-chlorophenyl)-
1,2-dimethyl-2H,4H-pyrrolo~3,4-d~2]benzazepine were added,
and the resulting solution was stirred for 20 minutes. The
25 excess peracid was discharged by the addition of saturated
aqueous sodium bisulfite solution, and the mixture was con-
centrated at reduced pressure. The residue was partitioned
between methylene chloride and water and basified with
concentrated ammonium hydroxide solution. The methylene
30 chloride solution was washed with brine, dried over anhydrous
sodium sulfate and concentrated at reduced pressure to a
yellow residue. Crystallization from ethyl acetate gave
8-chloro 6-(2-chlorophenyl)-1,4-dihydro-1,2-dimethylpyrrolo-
~3,4-d][2~benzazepin-3(2H)-one as pale yellow prisms,
3S mp 207-208Oc.
~,J~
:~Z~Z970
- 35 -
Example 10
a) In one portion, 2.0 g (5.8 mmol) of 8-chloro-6-(2-
chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d]C2]benzazepine
were added to an ice-cooled solution o~ 0.8 g (7.1 mmol)
of potassium t-butoxide in 30 ml of dry dimethylfoxmamide.
After stirring at 0C for 15 minutes, 0.65 ml (7.7 mmol)
of methyl bromoacetate was added, and the resulting solu-
tion was stirred for 5 minutes.iThe mixture was diluted
10 with water and extracted with ether. The ether solution
was washed with water, dried over anhydrous sodium sulfate,
and concentrated at reduced pressure to an oily residue.
Purification of the residue by column chromatography
(silica gel, 40 g; eluent, 5% ether in methylene chloride)
15 gave after crystallization from a mixture of ether and
petroleum ether 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-
pyrrolo[3,4-d][2]benzazepine-2-acetic acid methyl ester as
off-white prisms, mp 174-176C.
20 b) In one portion, 0.8 ml (7.0 mmol) of a 30/~ hydrogen
peroxide solution was added to a solution of 35 ml of 1%
concentrated sulfuric acid in acetic acid. After stirring
the solution for 1 hour, 2.0 g (4.8 mmol) of 8-chloro-6-
(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-acetic
25 acid methyl ester were added, and the resulting solution
was stirred for 30 minutes. The excess peracid was dis-
charged with the addition of saturated aqueous sodium bi-
sulfite solution, and the mixture was concentrated at
reduced pressure. The residue was partitioned between methy-
30 lene chloride and water and neutralized with concentratedammonium hydroxide solution. The methylene chloride solu-
tiOII was washed with brine, dried over anhydrous sodium
sulfate, and concentrated at reduced pressure to a residue
which crystallized in ethyl acetate to give 8-chloro-6-(2-
35 chlorophenyl)-1,4-dihydro-1-methyl-3-oxo-2H-pyrrolo[3,4-d]-
[2]benzazepine-2-acetic acid methyl ester as pale yellow
prisms, mp 221-223C. Recrystallization from ethyl acetate
gave colorless prisms, mp 223-224C.
~2~970
a) In one portion, 4.0 g (11.7 mmol) of 8-chloro-6-(2-
chlorophenyl)-1-methyl-2H,4H-pyrrolo~3,4-d]~2]benzazeplne
were added to an ice-cooled solution of 1.6 g (14.2 mmol)
of potassium t-butoxide in 60 ml of dry dimethylformamide.
After stirring at 0C for lS minutes, 1.4 g (15.0 mmol) of
2-chloroacetamide were added, and the resulting solution
was stirred for S ~ninutes. The mixture was diluted with
10 water and extracted with methylene chloride. The methylene
chloride solution was washed with water, dried over anhy-
drous sodium sulfate and concentrated at reduced pressure
to a red residue. Purification of the residue by column
chromatography (silica gel, 100 g; eluent, 50% ether in
15 tetrahydrofuran) gave 8-chloro-6-(2-chlorophenyl)-1-methyl-
2H,4H-pyrrolo[3,4-d][2]benzazepine-2-acetamide as a yellow
solid. Recrystallization from ethyl acetate gave colorless
needles, mp 142-145C.
~0 b) In one portion, 0.7 ml (6.2 mmol) of 30/O hydrogen
peroxide was added to a 1% solution of concentrated sul-
furic acid in acetic acid. After stirring for 1 hour, 1.7 g
(4.2 mmol) of 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-
pyrroloC3,4-d]~2]benzazepine-2-acetamide were ~dded, and the
25 resulting solution was stirred for 30 minutes. The excess
peracid was discharged by the addition of saturated aqueous
sodium bisulfite solution, and the mixture was concentrated
at reduced pressure. The residue was partitioned between
methylene chloride and water and neutralized with concen-
30 -trated ammonium hydroxide solution. The methylene chloride
solution was washed with brine, dried over anhydrous sodium
sulfate, and concentrated at reduced pressure. The residue
was crystallized from ethyl acetate to give 8-chloro-6-(2-
chlorophenyl)-1,4-dihydro-1-methyl-3-oxo-2H-pyrrolo~3,4-d]-
35 ~2]benzazepine-2-acetamide as colorless prisms, mp 221-222C.
3L2~2~70
- 37 -
Example 12
a) A solution of 4.0 g (9.6 mmol) of 8-chloro-6-~2-chloro-
phenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-acetic
acid methyl ester in 40 ml of tetrahydrofuran was added
dropwise to a solution of 0.8 g (21.0 mmol) of lithium alu-
minum hydride in 50 ml of tetrahydrofuran which was cooled
to -78C. When the addition was complete, the reaction mix-
ture was allowed to warm to 0C and stirred for 30 minutes.
10 The mixture was treated with 1 ml of water, 1 ml of a 3N
solution of aqueous sodium hydroxide and 3`ml of water. The
resulting precipitate was removed by filtration, and the
filtrate was concentrated at reduced pressure. The residue
crystallized from ether to yield 8-chloro-6-(2-chloro-
15 phenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepin-2-ethanol
as pale yellow prisms, mp 149-152C. Recrystallization from
a mixture of ether and methylene chloride gave white prisms,
mp 151-153~C.
20 b) In one portion, 0.58 ml (5.1 mmol) of 30% hydrogen
peroxide was added to a 1% solution of concentrated sul-
furic acid in acetic acid. After stirring for 1 hour, 1.3 g
(3.3 mmol) of 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-
pyrrolo[3,4 d][2]benzazepin-2-ethanol were added, and the
25 resulting solution was stirred ~or 30 minutes. The excess
~eracid was discharged with the addition of saturated
aqueous sodium bisulfite solution, and the mixture was
concentrated at reduced pressure. The residue was parti-
tioned between methylene chloride and water and neutrali-
30 zed with concentrated ammonium hydroxide solution. Themethylene chloride solution was washed with brine, dried
over anhydrous sodium sulfate, and concentrated at reduced
pressure to a yellow residue. Purifica-tion by column chroma-
tography (silica gel, 30 g; eluent, 3% methanol in methylene
35 chloride) gave in the first product band after crystalliza-
tion from a mixture of ether and methylene chloride 2-[2-
(acetoxy)ethyl]-8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1-
methylpyrrolo[3,4-d][2]benzazepin-3(2H)-one as colorless
~ZQ~970
- 38 -
prisms, mp 152-154C.
Further elution gave ln the second product band after
crystallization from a mixture of ethyl acetate and ether
8-chloro-6-(2-chlorophenyl)-1,4-dihydro-2-(2-hydroxyethyl)-
l-methylpyrrolo~3,4-d][2]benzazepin-3(2H)-on~ as colorless
prisms, mp 164-165C.
Example 13
In one portion, 0.7 g (2 mmol) of 8-chloro-6-(2-chloro-
phenyl)-3,4-dihydropyrrolo[3,4-d][2]benzazepin-1(2H)-one
was added to an ice-cooled solution of 2.6 g (15.8 mmol)
of trichloroacetic acid and 2.0 g (4.4 mmol) of lead tetra-
acetate in 30 ml of methylene chloride. After stirring for
1 hour, the mixture was neutralized with saturated aqueous
sodium bicarbonate solution. The methylene chloride solution
was washed with water, dried over anhydrous sodium sulfate
and concentrated at reduced pressure to a yellow residue.
Purification of the residue by column chromatography (silica
gel, 10 g; eluent, 5% methanol in methylene chloxide)
followed by crystallization from ether gave 8-chloro-6-(2-
chlorophenyl)-3,4-dihydro-3-hydroxypyrrolo[3,4-d][2]benza-
zepin-1(2H)-cne as pale yellow prisms, mp 221-222C.
Example 14
In one portion, 0.35 g (1 mmol) of 8-chloro-6-(2-chloro-
phenyl)-1,4-dihydropyrrolo[3,4-d][2]benzazepin-3(2H)-one
30 was added to an ice-cooled solution of 1.3 g (7.9 mmol) of
trichloroacetic acid and 1.0 g (2.2 mmol) of lead tetra-
ace-tate in 15 ml of methylene chloride. After stirring for
4 hours, the mixture was neutralized with saturated aqueous
sodium bicarbonate solution. The methylene chloride solu-
35 tion was washed with water, dried over anhydrous sodiumsulfate and concentrated at reduced pressure to a yellow
residue. Purification of the residue by column chromato-
graphy (silica gel, 10 g; eluent, 5% methanol in methylene
o
- 39 -
chloride) followed by crystallization from ether yave
8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1-hydroxypyrrolo-
[3,4-d][2]benzazepin-3(2H)-one as pale yellow prisms,
mp 247-249C.
Example 15
In one portion, 5.0 g (15.2 mmol) of 3-chloro-6-~2-
chlorophenyl)-2H,4H-pyrrolo[3,4~d][2]benzazepine were added
10 to a cooled solution of 20.0 g (120 mmol) of trichloro-
acetic acid and 14.0 g (31.6 mmol) of lead ~etraacetate in
50 ml of methylene chloride. The mixture was stirred at
room temperature for 4 hours and then diluted with methy-
lene chloride and water. The methylene chloride solution
15 was washed with saturated aqueous sodium bicarbonate solu-
tion, dried over anhydrous sodium sulfate and concentrated
at reduced pressure to a green residue. Purification of the
residue by column chromatography (silica gel, 100 g; eluent,
5% methanol in methylene chloride) gave in the first pro~
20 duct band after crystallization from ether ~3-chloro-6-(2-
chlorophenyl)pyrrolo~3,4-d][2]benzazepin-1,3(2H,4H)-dione
as yellow prisms, mp 224-225C.
Further elution gave in the second product band after
25 crystallization from ether 8-chloro-6-(2-chlorophenyl)-
3,4-dihydro-3-hydroxypyrrolo[3,4-d][2]benzazepin-1(2H)-one
as pale yellow prisms, mp 222-223C.
Still further elution gave in the third product band
30 after crystallization from ether 8-chloro-6-(2-chloro-
phenyl)-1,4-dihydro-1-hydroxypyrrolo[3,4-d][2]benzazepin-
3(2H)-one as pale yellow prisms, mp 247-249C.
Example 16
Portionwise, 12.0 g (27 mmol) of lead tetraacetate
were added over 2 hours to a solution of 6.0 g (12.2 mmol)
of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benza-
I
l~a~
- 40 -
zepine in 120 ml of acetic acid. After stirring for an
additional 2 hours, hydrogen sulfide gas was bubbled into
the solution. The resulting precipitate was removed by
filtration over Celite. The filtrate was neutralized by
the addition of saturated aqueous sodium carbonate solution
and extracted with methylene chloride. The methylene chlo-
ride solution was washed with water, dried over anhydrous
sodium sulfate and concentrated at reduced pressure to give
a brown oil. Purification by column chromatography (silica
10 gel, 100 g; eluent, 100% methylene chloride to 20% ether in
methylene chloride gradient) gave in the first product band
an off-white solid. Recrystallization from a mixture of
methylene chloride, ether, and petroleum ether gave 8-chloro-
6-(2-chlorophenyl)-2H,4H-pyrroloZ3,4-d][2]benzazepine-1,3-
diol diacetate as colorless needles, mp 189-190C.
Further elution gave 1.95 g of a foam which crystalli-
zed from a mixture of ether and petroleum ether to give
8-chloro-6-(2-chlorophenyl)-3-acetoxy-3,4-dihydropyrrolo-
20 t3,4-d][2]benzazepin-1(2H)-one as colorless prisms, mp
172-174C.
Continued elution gave fine needles. Recrystallization
from a mixture of ether and methylene chloride gave 8-
25 chloro-6-(2-chlorophenyl)-1-acetoxy-1,4-dihydropyrrolo-
[3,4-d][2]benzazepin-3(2H)-one, mp 219-221C.
Example 17
A solution of 0.3 g (O.9 mmol) of 8~chloro-6-(2-
chlorophenyl)-3-hydroxy-3,4-dihydropyrrolo[3,4-d][2]benza-
zepin-1(2H)-one, 0.3 g (1.3 mmol) of benzoic acid anhydride,
and 0.3 g (2.5 mmol) of dimethylaminopyridine in a mixture
of 30 ml of methylene chloride and 10 ml of tetrahydrofuran
35 was stirred at 0C for 1 hour. The mixture was diluted with
water, washed successively with cold, dilute hydrochloric
acid, saturated aqueous sodium bicarbonate solution, and
brine and dried over anhydrous sodium sulfate. The methy-
~2~ 0
- 41 ~
lene chloride solution was concentrated at reduced pressure.
The residue was purified by column chromatography (silica
gel, 10 g; eluent, 5% ether in methylene chloride) to give
8-chloro-6-(2-chlorophenyl)-3-~benæoyloxy)-3,4-dihydro-
pyrrolo[3,4-d]~2]benzazepin-1(2H)-one as colorless crystals.
Recrystallization from ether gave colorless crystals, mp
140-142C.
Example 18
A solution of 0.6 g of 8-chloro-6-(2-chlorophenyl)-
3-acetoxy-3,4-dihydropyrrolo[3,4-d][2]benzazepin-1(2H)-one
and 3 ml of a lM methanolic solution of methanesulfonic
acid in 10 ml of methanol was stirred at room temperature
15 for 30 minutes. The solution was concentrated at reduced
pressure to half the volume, diluted with ether, and the
resulting precipitate was collected by filtration to give
orange crystals. Recrystallization from a mixture of
methanol and ether gave 8-chloro-6-(2-chlorophenyl)-3,4-
20 dihydro-3-methoxypyrrolo[3~4-d]~2]benzazepin-l(2H)-one
methanesulfonate as off-white prisms, mp 157-160C.
Example 19
A solution of 0.1 g (0.25 mmol) of 8-chloro-6-(2-
chlorophenyl)-1-acetoxy-1,4-dihydropyrrolo[3,4-d][2]benza-
zepin-3(2H)-one and 1 ml of a lM methanolic solution of
methanesulfonic acid was allowed to stand at~`room tempe-
rature for 36 hours. The mixture was diluted with ether,
30 and the resulting precipitate was collected by filtration
to give 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1-methoxy-
pyrrolo[3,4-d][2]benzazepin-3(2H)-one methanesulfonate.
Recrystallization from a mixture of ether and methanol gave
fine needles, mp 185-187C.
~L2~2970
- 42 -
Example 20
~ solution of 1.5 g (3.4 mmol) of 8-chloro-6-(2-
chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepin-1,3-diol
diacetate in 25 ml of a lM methanol solution of methane-
sulfonic acid was refluxed for 6 h. The reaction was
cooled, made basic by the addition of saturated aqueous
- sodium bicarbonate and extracted with methylene chloride.
The methylene chloride solution was dried over anhydrous
10 sodium sulfate and concentrated at reduced pressure. The
resid~e was dissolved in 4 ml of a lM methanol solution
of methanesulfonic acid, diluted with ether until turbid
and filtered. The filtrate was made basic with saturated
aqueous sodium bicarbonate. The ether solution was dried
15 over anhydrous sodium sulfate and concentrated at reduced
pressure to give 8-chloro-6-(2-chlorophenyl)-3,4-dihydro-
3-methoxypyrrolo[3,4-d][2]benzazepin-1(2H)-one as off
white crystals, mp 192-194~C. The presence of the isomeric
8-chloro-6-(2-chloropAenyl)-1,4-dihydro-1-methoxypyrrolo-
20 [3,4-d][2]benzazepin-3~2H)-one was noted by the thin layer
chromatography but was not isolated.
The methanesulfonate salt of 8-chloro-6-(2-chloro-
phenyl)-1,4-dihydro-3-methoxypyrrolo[3,4-d][2~benzazepin-
25 1(2H)-one was prepared by dissolving the free base in an
excess of methanolic methanesulfonic acid and isolated by
precipitating the salt with the addition of ether. Re-
crystallization from a mixture of methanol and ether gave
the salt as colorless crystals, mp 157-160C.
Example 21
In one portion, 1.8 ml (20 mmol) of phosphorous tri-
chloride were added to a solution of 0.9 g (2.5 mmol) of
35 8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo[3,4-d][2~-
benzazepin-3(2H)-one-5-oxide in 180 ml of methylene chloride.
The mixture was refluxed for 1 hour and then concentrated
at reduced pressure. The residue was dissolved in methylene
.,
~2~297~
- A3 -
chloride and neutralized with saturated a~ueous sodium
bicarbonate solution. The methylene chloride solution was
dried over anhydrous sodium sulfate and concentrated at
reduced pressure to give 8-chloro-6-(2-chlorophenyl) 1,4-
dihydropyrrolo[3,4-d]C2]benzazepin-3(2~)-one as an orange
solid. Recrystallization from ethyl acetate gave pale
yellow prisms of a 0.25 mole hydrate, mp 255-256C.
Example 22
In one portion, 2 ml (2.3 mmol) of phosphorous tri-
chloride were added to a solution of 1.0 g (2.7 mmol) of
8-chloro-6-(2-chlorophenyl)-3,4-dihydropyrrolo[3,4-d][2]-
benzazepine-1(2H)-one-5-oxide in 200 ml of methylene chlo-
15 ride and reflu~ed for 1 hour. The mixture was concentratedat reduced pressure. The residue was dissolved in methylene
chloride and neutralized with saturated aqueous sodium
bicarbonate solution. The methylene chloride solution was
dried over anhydrous sodium sulfate and concentrated at
20 reduced pressure to give a dark red residue. Purification
of the residue by column chromatography (silica gel, 20 g;
eluent, 5% methanol in methylene chloride) followed by
crystallization from ethyl`acetate gave 8-chloro-6-(2-
chlorophenyl)-3,4-dihydropyrrolo~3,4-d]~2]benzazepin-1(2H)-
25 one as pale yellow prisms solvated with 0.5 mole ethylacetate, mp 195-197C.
~Z~;~970
- 44 -
Example A
Tablet Formulation (Direct compression)
5 Item Ingredients mg/tablet
1. 8~chloro-6-(2-chlorophenyl)-
1,4-dihydropyrrolo[3,4-d]-
[2]benzazepin-3(~H)-one 1 5 10 25
or
8-chloro-6-(2-chlorophenyl)-
1,4-dihydro-1-methylpyrrolo-
[3,4-d][2]benzazepin-3~2H)-one
2. Lactose 221 217 212 181
3. Avicel 45 45 45 55
15 4. Direct Compression Starch 30 30 30 35
5. Magnesium Stearate _ 3 3 4_
Weight of tablet 300 300 300 300
Procedure:
1. Mix Item 1 with an equal amount of lactose. Mix well.
2. Mix with Items 3 and 4 and the remaining amount of
Item 2. Mix well.
26
3. Add magnesium stearate and mix for 3 minutes.
4. Compress on a suitable press equipped with appropriate
punches.
* Trademark
~Z~2~0
- 45 _
Example B
Tablet Formulation (Wet granulation)
5 Item Ingredients mg/tablet
1. 8-chloro-6-(2-chlorophenyl)-
1,4-dihydropyrroloC3,4-d]-
[2]benzazepin-3(2H)-one1 5 10 25
or
8-chloro-6-(2-chlorophenyl)-
1,4-dihydro-1-methylpyrrolo-
~3,4-d]~2]benzazepin-3(2H)-one
2. Lactose 202 232 261 280
3. Modified Starch 25 35 45 55
15 4- Pregelatinized Starch20 25 30 35
5. Distilled Water q.s.
6. Magnesium Stearate 2 3 4 5
Weight of tablet 250 300 350 400
20 Procedure:
Mix Items 1-4 in a suitable mixer.
2. Granulate with sufficient distilled water to proper
consistency. Mill.
3. Dry in a suitable oven.
4. Mill and mix with magnesium stearate for 3 minutes.
5. Compress on a suitable press equipped with appropriate
punches.
970
- 46 -
Example C
Capsule Formulation
5 Item Ingredients mg/capsule
1. 8-chloro-6-(2-chlorophenyl)-
1,4-dihydropyrrolo~3,4-d]-
~2]benzazepin-3(2H)-one1 510 25
or
8-chloxo-6-(2-chlorophenyl)-
1,4-dihydro-1-methylpyrrolo-
~3,4-d]~2]benzazepin-3~2H)-one
2. Lactose 203 193.5 328 372.5
3. Starch 30 3540 30
15 4- Talc * 15 1520 20
5. Aerosol OT 1 1.5 2 2.5
Capsule fill weight250 350400 450
Procedure:
1. Mill Items 1, 2, 3, and 5 in a suitable mixer. ~ill.
2. Add talc and mix well.
25 3. Encapsulate on suitable equipment.
* Trademark
P~
